The respiratory tract is a major portal of entry for many pathogens. Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections. Not only do IAV-induced illnesses have a significant economic impact, but there are also ~36,000 deaths and ~1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought be the result of significant immunopathology. It is well defined that IAV strains vary in the severity of lung disease they induce. Thus, the long-term goal of our laboratory is to understand the fine balance between protection and host damage caused by immune responses to IAV infection. The initial lines of defense against pathogens in the lungs include alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. However, the role of the mast cell has been under explored during respiratory viral infection. Importantly, our data demonstrate that mast cells are critical for initiating the inflammatory immunopathology induced by influenza virus in a virus strain-specific manner; however, mast cells did not play a critical role in the clearance of IAV from the respiratory tract. Furthermore, others have reported that during IAV infection of humans significantly elevated levels of histamine can be detected coincident with IAV induced symptoms. Thus, mast cells are likely to participate in the immune response to IAV infection, but what their role is has not been elucidated. This proposal has three specific aims which will test the role of mast cells during IAV infection and elucidate the molecular mechanisms responsible for their activation, recruitment, and activity. In specific aim 1, we will identify which receptors modulate mast cell activity in response to IAV and determine the role of newly recruited mast cell progenitors in the IAV-induced lung inflammation. In specific aim 2, we will define the key mast cell effectors that are critical for inducing the inflammation- induced pulmonary injury during respiratory IAV infection. In specific aim 3, we will define the role of the IAV hemaggultinin in initiating the mast cell-dependent IAV immune response. Completion of these three aims will offer novel insights into the mechanisms of mast cell activation and function during respiratory viral infection. In conclusion, understanding mast cells and IAV strain specificity contributions to the inflammatory response will not only be crucial in the development and appropriate use of novel host-targeted therapeutics to limit IAV-induced host damage and morbidity, but will also provide novel regions of viral proteins which could be targeted by novel anti-viral therapeutics.